U.S. patent number 8,942,809 [Application Number 12/885,223] was granted by the patent office on 2015-01-27 for systems and methods for improving a cognitive function.
The grantee listed for this patent is Souhile Assaf, Mandar Jog, Jessie Y. Shen. Invention is credited to Souhile Assaf, Mandar Jog, Jessie Y. Shen.
United States Patent |
8,942,809 |
Assaf , et al. |
January 27, 2015 |
Systems and methods for improving a cognitive function
Abstract
In many aspects, the invention relates to systems and methods
for providing cognitive therapy through stimulation of activating
and inhibiting neurons in the brain, thereby modulating neural
firing rhythms. The stimulation of neurons is controlled through a
feedback process whereby neuron firing rhythms are altered based on
naturally occurring electrical and chemical activity in the brain.
Neurons in specific regions of the brain may be targeted in order
to establish neural signaling pathways and establish communication
between these regions.
Inventors: |
Assaf; Souhile (London,
CA), Shen; Jessie Y. (London, CA), Jog;
Mandar (London, CA) |
Applicant: |
Name |
City |
State |
Country |
Type |
Assaf; Souhile
Shen; Jessie Y.
Jog; Mandar |
London
London
London |
N/A
N/A
N/A |
CA
CA
CA |
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Family
ID: |
39268860 |
Appl.
No.: |
12/885,223 |
Filed: |
September 17, 2010 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20110009922 A1 |
Jan 13, 2011 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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11824077 |
Jun 28, 2007 |
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60806053 |
Jun 28, 2006 |
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60910297 |
Apr 5, 2007 |
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60910391 |
Apr 5, 2007 |
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Current U.S.
Class: |
607/45 |
Current CPC
Class: |
A61N
1/36082 (20130101); A61N 1/32 (20130101) |
Current International
Class: |
A61N
1/36 (20060101) |
Field of
Search: |
;607/45 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Schaetzle; Kennedy
Attorney, Agent or Firm: Krupnik; Eduardo
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATION
This application is a continuation of U.S. application Ser. No.
11/824,077, filed Jun. 28, 2007, which claims priority to U.S.
Provisional Patent Application No. 60/806,053, filed Jun. 28, 2006,
U.S. Provisional Patent Application No. 60/910,297 filed Apr. 5,
2007, and U.S. Provisional Patent Application No. 60/910,391, filed
Apr. 5, 2007, the entire contents of each of which are incorporated
herein by reference.
Claims
What is claimed is:
1. A method of improving a cognitive function in a patient,
comprising: (a) receiving a set of inputs from a first region in a
patients brain, (b) correlating the set of inputs with a set of
neurophysiological markers of a cognitive function, and (c)
improving the cognitive function in the patients brain by inducing
a response in a second region of the brain, which response is
selected based upon the correlations of step (b), wherein the first
region in the brain exhibits activity indicative of memory
readiness.
2. The method of claim 1, wherein the cognitive function includes
memory.
3. The method of claim 1, further comprising determining an
alertness level.
4. The method of claim 3, wherein the response is selected further
based upon the alertness level.
5. The method of claim 3, wherein a location of the second region
is based on the alertness level.
6. The method of claim 3, wherein the alertness level is based on a
state of consciousness of the patient including at least one of
awake, alert, sleep and unconsciousness.
7. The method of claim 3, wherein the alertness level is based on
whether the patients brain is performing at least one of
information processing, information consolidation and information
recall.
8. The method of claim 3, wherein the alertness level is determined
by a user.
9. The method of claim 3, wherein the alertness level is determined
based on the set of inputs.
10. The method of claim 9, wherein the set of inputs includes at
least one of theta activity, delta activity, and alpha activity,
recorded from hippocampus and neocortex, and rhythmic discharges
from supramammillary nucleus and medial septum.
11. The method of claim 9, wherein the patient exhibits at least
two alertness levels.
12. The method of claim 11, wherein improving the cognitive
function comprises inducing at least two different responses that
correspond to the at least two alertness levels.
13. The method of claim 12, wherein improving the cognitive
function comprises inducing neurons in the second region of the
brain to generate hippocampal theta rhythm when alertness level is
set high, and inducing neurons in the second region of the brain to
generate hippocampal sharp waves when alertness level is set
low.
14. The method of claim 1, wherein receiving a set of inputs
includes measuring at least one of an electrical signal and a
chemical signal.
15. The method of claim 14, wherein the first region includes at
least one of hippocampus and neocortex.
16. The method of claim 14, wherein the set of neurophysiological
markers includes at least one of hippocampal theta and cortical
theta activity.
17. The method of claim 1, wherein inducing a response includes
delivering at least one of an electrical signal and a chemical
signal to neurons in the second region in the brain.
18. The method of claim 17, wherein the cognitive function is
improved by inducing at least one of a hippocampal theta rhythm,
hippocampal sharp waves and gamma activity.
19. The method of claim 18, wherein the theta rhythm is induced by
stimulating at least one of activating neurons and inhibiting
neurons in the second region.
20. The method of claim 18, wherein the hippocampal sharp waves are
induced by stimulating at least one of activating neurons and
inhibiting neurons in the second region.
21. The method of claim 1, wherein the second region includes at
least one of hippocampus, medial septum, fornix, fimbria,
supramammillary nucleus, posterior hypothalamus, nucleus basalis
Meynert, nucleus pontis oralis and median raphe nucleus.
22. The method of claim 18, wherein the gamma activities are
induced by stimulating at least one of activating neurons and
inhibiting neurons in the second region.
23. The method of claim 1, wherein inducing a response includes
inducing neurons in the second region of the patients brain to
generate a signal that is substantially similar to the at least one
of the set of inputs.
24. The method of claim 1, wherein the cognitive function includes
positive memory events.
25. The method of claim 24, further comprising predicting negative
memory events based on the inputs from the first region, and
applying a signal that is substantially similar to the activity
observed at the second region during positive memory events.
26. The method of claim 24, further comprising building a database
of positive memory events and negative memory events based on a set
of cognitive exercises performed by the patient.
27. The method of claim 1, wherein at least one of the first region
and the second region comprises a neural signaling pathway that
includes neurons connecting at least two of CA1, CA2, CA3, Dentate
Gyrus, Entorhinal Cortex, Hilus, and subiculum.
28. The method of claim 1, wherein at least one of the first region
and the second region comprises a neural signaling pathway that
includes neurons connecting at least two of posterior nucleus
hypothalamus, supramammillary nucleus, medial septum, hippocampus,
neocortex.
29. The method of claim 1, wherein at least one of the first region
and the second region comprises a neural signaling pathway that
includes the Perforant Path, Schaffer Collateral Pathway, and
Associational Commissural Pathway.
30. A system for improving a cognitive function, comprising: a
plurality of implantable elements for sensing and delivering
signals within a brain; control circuitry configured to: receive a
set of inputs from at least one of the plurality of implantable
elements, correlate the set of inputs with a set of
neurophysiological markers of a cognitive function, determine a
response based on said correlations, and induce the response in the
brain using at least one of the plurality of implantable elements;
and at least one training mode and at least one functioning
mode.
31. The system of claim 30, wherein the implantable elements
include electrodes capable of recording and generating electrical
signals.
32. The system of claim 30, wherein the implantable elements
include sensors capable of sensing chemical concentration.
33. The system of claim 30, wherein the implantable elements
include catheters for delivering chemicals to the brain.
34. The system of claim 33, wherein the implantable elements
include a reservoir for supplying chemicals to the brain.
35. The system of claim 30, wherein the implantable elements
include at least one short term electrode, and at least one long
term electrode, and the control circuitry is further configured to
determine if the short term electrode is functioning, in response
to determining that the short term electrode is functioning,
receive a first set of inputs from the at least one short term
electrode and a second set of inputs from the at least one long
term electrode, and associate one or more of the first set of
inputs with one or more of the second set of inputs in response to
determining that the short term electrode has failed, infer a first
set of inputs based on the second set of inputs.
36. The system of claim 30, further comprising a database of
activities observed in the brain during positive memory events.
37. The system of claim 36, wherein the control circuitry is
further configured to: populate the database of activities during
the training mode, and apply the activities in the database to the
brain during the functioning mode.
38. The system of claim 36, further comprising a database of
activity observed in the brain during negative memory events.
39. The system of claim 38, wherein the control circuitry is
further configured to: populate both databases during the training
mode, and identify negative memory events based on referencing the
inputs from the first region to the database of negative memory
events and apply the corresponding activity from the database of
positive memory events during function mode.
40. A method of improving a cognitive function in a patient,
comprising: (a) receiving a set of inputs from a first region in
the patient's brain, (b) correlating the set of inputs with a set
of neurophysiological markers of a cognitive function, (c)
determining an alertness level of the patient based on the set of
inputs, and (d) improving the cognitive function in the patients
brain by inducing a response in a second region of the brain, which
response is selected based upon the correlations of step (b),
wherein when the patient exhibits at least two alertness levels,
improving the cognitive function comprises inducing at least two
different responses that correspond to the at least two alertness
levels, and wherein inducing at least two different responses
comprises inducing neurons in the second region of the brain to
generate hippocampal theta rhythm when alertness level is set high,
and inducing neurons in the second region of the brain to generate
hippocampal sharp waves when alertness level is set low.
41. A method of improving a cognitive function in a patient,
comprising: (a) receiving, a set of inputs from a first region in a
patient's brain, (b) correlating the set of inputs with a set of
neurophysiological markers of a cognitive function, and (c)
improving the cognitive function in the patients brain by inducing
a response in a second region of the brain by delivering at least
one of an electrical signal and a chemical signal to neurons in the
second region in the brain, which response is selected based upon
the correlations of step (b), wherein the cognitive function is
improved by inducing at least one of a hippocampal theta rhythm,
hippocampal sharp waves and gamma activity, and wherein the theta
rhythm is induced by stimulating at least one of activating neurons
and inhibiting neurons in the second region.
42. A method of improving a cognitive function in a patient,
comprising: (a) receiving a set of inputs from a first region in a
patient's brain, (b) correlating the set of inputs with a set of
neurophysiological markers of a cognitive function, and (c)
improving the cognitive function in the patients brain by inducing
a response in a second region of the brain by delivering at least
one of an electrical signal and a chemical signal to neurons in the
second region in the brain, which response is selected based upon
the correlations of step (b), wherein the cognitive function is
improved by inducing at least one of a hippocampal theta rhythm,
hippocampal sharp waves and gamma activity, and wherein the
hippocampal sharp waves are induced by stimulating at least one of
activating neurons and inhibiting neurons in the second region.
43. A method of improving a cognitive function in a patient,
comprising: (a) receiving a set of inputs from a first region in a
patient's brain, (b) correlating the set of inputs with a set of
neurophysiological markers of a cognitive function, and (c)
improving the cognitive function in the patients brain by inducing
a response in a second region of the brain by delivering at least
one of an electrical signal and a chemical signal to neurons in the
second region in the brain, which response is selected based upon
the correlations of step (b), wherein the cognitive function is
improved by inducing at least one of a hippocampal theta rhythm,
hippocampal sharp waves and gamma activity, and wherein the gamma
activities are induced by stimulating at least one of activating
neurons and inhibiting neurons in the second region.
44. A system for improving a cognitive function, comprising: a
plurality of implantable elements for sensing and delivering
signals within a first region of a brain; and control circuitry
configured to: receive a set of inputs from at least one of the
plurality of implantable elements, correlate the set of inputs with
a set of neurophysiological markers of a cognitive function,
determine a response based on said correlations, and induce the
response in a second region of the brain using at least one of the
plurality of implantable elements, wherein the implantable elements
include at least one short term electrode, and at least one long
term electrode, and the control circuitry is further configured to:
determine if the short term electrode is functioning, in response
to determining that the short term electrode is functioning,
receive a first set of inputs from the at least one short term
electrode and second set of inputs from the at least one long term
electrode, and associate one or more of the first set of inputs
with one or more of the second set of inputs in response to
determining that the short term electrode has failed, infer a first
set of inputs based on the second set of inputs.
Description
FIELD OF INVENTION
The present invention relates to techniques for providing therapy
to improve cognitive function such as learning and memory.
BACKGROUND OF THE INVENTION
Cognitive functions depend on different regions in the brain to
process and communicate information with each other. The
information is typically in the form of electrical and chemical
signals that are communicated along neural signaling pathways
between these regions. The neural signaling pathways are composed
of electrically active brain cells called neurons. Many
neurological disorders cause the degeneration of neurons in the
brain and can therefore impair one or more cognitive functions.
Memory is a cognitive function that is facilitated in, among other
places, the hippocampus and neocortex. During memory formation,
information is transferred through neural signaling pathways both
within and outside of the hippocampus. In some neurodegenerative
diseases, including Alzheimer's disease, neurons in the hippocampus
and neocortex degenerate, thereby disrupting communication along
the neural signaling pathways.
There are currently no effective treatments for curing
neurodegenerative disorders like Alzheimer's. Many researchers and
scientists have proposed methods for implanting electrodes and
catheters deep in the brain to stimulate desired regions including
the hippocampus. However, these techniques simply provide jolts of
electrical current to the brain that may even cause instability in
those regions. They also suffer from a number of drawbacks
including undesirable side effects, a short lifetime,
unpredictability, and a lack of reproducibility.
Accordingly, there is a need for systems and methods for improving
cognitive function through therapy.
SUMMARY OF THE INVENTION
The present invention is directed to systems and methods for
improving cognitive function in the brain, especially in the event
of the degeneration of neurons along neural signaling pathways. For
purposes of clarity, and not by way of limitation, the systems and
methods may be described herein in the context of improving
particular cognitive functions that are associated with particular
regions of the brain, such as memory with reference to the
hippocampus and neocortex. However, it may be understood that the
systems and methods of the present invention may be applied to
improve any other cognitive function associated with any portion of
the nervous system.
The systems and methods provide for intelligently controlling the
neural firing rhythms in a region of the brain based on naturally
occurring measures of cognitive activity such as neurophysiological
markers (e.g., electrical and chemical activity) in that region or
in a related region.
The system includes implantable elements and control circuitry for
detecting electrical and chemical activity in the brain associated
with a particular cognitive function and correlating the activity
with a desired measure of a cognitive function. For example,
electrical activity during a memory recall may be correlated with
the nature of the memory recall (i.e., positive or negative
recall). The nature of the memory recall, however, may also be
measured with one or more neurophysiological markers (e.g., gamma
rhythms). The electrical and/or chemical activity corresponding to
a desired value of the neurological marker may be applied to a
desired region of the brain to improve the cognitive function. As
an example, hippocampal theta rhythm is necessary for memory
formation, particularly for information processing. The theta
rhythm includes extra-cellular currents that lie within a
characteristic frequency range of about 4-8 Hz. The systems and
methods provide for modulating the theta rhythm of the hippocampus
by applying suitable electrical and chemical signals. These signals
are controlled by continuously measuring other naturally occurring
characteristics that the theta rhythms are associated with such as
gamma oscillations in the hippocampus and neocortex. As another
example, gamma (synchronicity) rhythm of the neocortex also plays a
role in memory formation and other cognitive functions. The systems
and methods also provide for recording and/or modulating the gamma
rhythm of the neocortex by applying suitable electrical and
chemical signals. Generally, the systems and methods provide for
recording and/or modulating activity from one or more regions of
the brain to improve one or more cognitive functions.
In one aspect the systems and methods described herein are methods
for improving cognitive function in a patient. The method includes
the steps of receiving a set of inputs from a first set of at least
one region in a patient's brain, correlating the set of inputs with
a set of neurophysiological markers of a cognitive function, and
improving the cognitive function in the patient's brain by inducing
a response in a second region of the brain, which response is
selected based upon the correlations. In certain embodiments, the
first region is the same as the second region.
In certain embodiments, the method further comprises determining an
alertness level of the patient. The location of at least one of the
first and second regions may be selected based on the alertness
level. In certain embodiments, the response is selected based on
the alertness level of the patient. In certain embodiments, the
patient may exhibit two alertness levels that are determined based
on whether the patient is awake or asleep. In such embodiments, the
method comprises delivering at least two different responses that
correspond to at least two alertness levels. The different
responses may also be induced depending on the patient's alertness
level. In certain embodiments, the alertness level is determined
based on the set of inputs, such as theta rhythm.
In certain embodiments, the alertness level is high (e.g., this may
indicate that the subject is awake and the therapy may be needed to
promote information processing), and improving the cognitive
function comprises inducing the neurons in the second region of the
patient's brain to induce hippocampal theta rhythm. In certain
embodiments, the alertness level is low (e.g., this may indicate
that the subject is drowsy or asleep and the therapy may be needed
to promote information consolidation), and improving the cognitive
function comprises inducing the neurons in the second region of the
patient's brain to induce hippocampal sharp waves. The alertness
level may be determined based on a state of consciousness of the
patient including awake and/or alert and/or sleep and/or
unconsciousness. In certain embodiments, the alertness level is
determined based whether the patient's brain is processing
information or consolidating information or recalling information.
In certain embodiments, the alertness level is user configurable,
In certain embodiments, the alertness level is determined by a
user.
In certain embodiments, the type of therapy or response is
determined by the patient or care-giver. In one example, if the
patient is going to sleep, the patient or the care-giver may set
the therapy to a memory consolidation mode. During the day, the
patient or the care-giver may set the therapy to information
processing mode.
In certain embodiments, providing a inducing a response includes
delivering an electrical signal and/or a chemical signal to neurons
in the second region of the patient's brain to induce a desired
neurophysiological response. In certain embodiments, the first
and/or second regions include portions of the patient's brain that
enable memory functions and are selected based on the alertness
level.
In certain embodiments the systems and methods induce hippocampal
theta rhythm by stimulating/activating neurons and/or inhibiting
neurons in the second region. In certain embodiments, the neurons
in the second region are located in the hippocampus and/or fornix
and/or medial septum and/or supramammillary nucleus and/or
posterior nucleus hypothalamus and/or nucleus pontis oralis and/or
median raphe nucleus and/or neocortex and/or other portions of the
brain and nervous system.
In certain embodiments, inducing a response includes delivering one
or more electrical signals and/or one or more chemical signals to
neurons in the second region of the patient's brain to induce
activity (such as electrical and chemical signals) that may measure
the performance of a memory process. The metric may include
hippocampal sharp waves. In certain embodiments, the hippocampal
sharp waves are induced by stimulating activating neurons and/or
inhibiting neurons in the second region. In certain embodiments,
the neurons in the second region are located CA1 and/or CA3.
In certain embodiments, hippocampal theta can be elicited by
electrical stimulation of the supramammillary nucleus. The
hippocampal theta may also be elicited by chemical stimulation with
a carbachol injection. The hippocampal theta may also be reversibly
inhibited by a procaine injection.
In certain embodiments, receiving a set of inputs includes
measuring an electrical signal and/or a chemical signal. In certain
embodiments, the electrical signal includes at least one of theta
signal, a gamma signal, neocortical synchrony, delta activity,
alpha activity recorded from the hippocampus and/or neocortex, and
rhythmic discharges recorded from supramamillary nucleus and medial
septum. The inputs may include any electrical, chemical,
morphological and physical (e.g., blood flow) activity or signals
in the brain. In certain embodiments, providing therapy includes
delivering an electrical signal and/or a chemical signal to induce
neurons in the second region of the patient's brain to generate a
signal that is substantially similar to the at least one of the set
of inputs.
In certain embodiments, neurophysiological markers are measures of
a cognitive function. Neurophysiological markers may include
electrical activity (e.g., neural firing patterns such as
hippocampal theta activity and cortical theta activity) and
chemical activity (e.g., neurotransmitters and other chemicals
capable of mimicking neurotransmitters) in the brain. The
neurophysiological markers may also include morphological and
structural measurements of the different regions in the brain. The
neurophysiological markers may further include other physical
activities in the human body and the brain such as blood flow. As
an example, functional MRI measurements may be used to track blood
flow in the brain and are capable of identifying and measuring
cognitive function based on the region receiving blood. In certain
alternative embodiments, neurophysiological markers may also be
linked to a behavioral trait or patient's speech and
communication.
In certain embodiments, positive and negative memory recall events
may include neurophysiological markers including at least one of
hippocampal theta and cortical theta activity. In certain
embodiments, correlating the set of inputs with a set of
neurophysiological markers includes performing one or more
cognitive exercises to associate one or more inputs with one or
more neurophysiological markers. In such embodiments, during
cognitive exercises, the implantable elements (such as electrodes)
at recording sites and stimulation sites are recording the local
activity. The recorded local activity at the recording sites may be
associated with positive or negative recall events and to predict
negative events. A database of positive events and the
corresponding recorded activity may be built. In certain
embodiments, when a negative event is predicted, activity recorded
at the stimulation sites during positive events is superimposed on
the local activity of the corresponding stimulation sites. In
certain embodiment, the activity superimposed is an average of the
events collected in the positive database.
In certain embodiments, the systems and methods further include
steps of predicting negative memory events based on the inputs from
the first set of at least one region. In such embodiments, the
therapy may be applied by generating a signal that is substantially
similar to the activity observed at the second set of at least one
region during positive memory events. The systems and methods
further include building a database of positive and negative memory
events based on a set of cognitive exercises performed by the
patient. The systems may include control circuitry configured to
populate the databases and identify negative memory events based on
referencing the inputs from the first region to the database of
negative memory events and apply the corresponding activity from
the database of positive memory event.
In certain embodiments, the system further builds an inference to
differentiate the input conditions that each negative event
triggers, such that the modulating pattern is determined based on
successful trials with similar input conditions.
In certain embodiments, the systems and methods use recording sites
that are not degenerating and stimulation sites that are continuing
to fail. The system may be regularly trained by repeated cognitive
exercises, such that the superimposed pattern may eventually
replace the functions of the local neurons that have stopped
functioning.
In certain embodiments, the neural signaling pathway include
neurons connecting at least two of CA1, CA2, CA3, Dentate Gyrus,
Entorhinal Cortex, Hilus, and subiculum. In certain embodiments,
the neural signaling pathway includes the Perforant Path, Schaffer
Collateral Pathway, and Associational Commissural Pathway. In
certain embodiments, the neural signaling pathway includes
posterior nucleus hypothalamus, supramammillary nucleus, medial
septum, hippocampus, and neocortex.
In one aspect, a system for improving a cognitive function
comprises a plurality of implantable elements for sensing and
delivering signals within a brain, and control circuitry connected
to the implantable elements. The control circuitry may be
configured to receive a set of inputs from at least one of the
plurality of implantable elements and correlate the set of inputs
with a set of neurophysiological markers of a cognitive function.
The control circuitry may be configured to determine a response
based on the correlations, and induce the response in the brain
using at least one of the plurality of implantable elements.
In certain embodiments, the implantable elements include electrodes
capable of recording and generating electrical signals. In certain
embodiments, the implantable elements include sensors capable of
sensing chemical concentration. In certain embodiments, the
implantable elements include catheters for delivering chemicals to
the brain.
In certain embodiments, the implantable elements include at least
one electrode recording information indicative of the memory
activity, and at least one electrode that is suitable for long term
implantation. In one embodiment, the electrode recording indicative
activity is an electrode recording from single neuron or small
cluster of neurons. Such an electrode may have a limited lifetime
due to glial scarring or surface degradation of contact surfaces.
The long term implantation electrode recording local field
potential, intracortical EEG, or subdural EEG lasts longer due to a
larger contact surface. In certain embodiments, an inference engine
is capable of extracting single neuron activity from the long term
electrodes.
In certain embodiments, the system includes a short term electrode
and a long term electrode. In such embodiments, the control
circuitry may be configured to determine if the short term
electrode is function. In response to determining that the short
term electrode is function, the control circuitry is configured to
receive a first set of inputs from at least the short term
electrode and a second set of inputs from at least the long term
electrode. The control circuitry may also be configured to
associate one or more of the first set of inputs with one or more
of the second set of inputs. In certain embodiments, in response to
determining that the short term electrode has failed, the control
circuitry is configured to infer a first set of inputs based on the
second set of inputs.
In one aspect, a method of improving a cognitive function in a
patient comprises receiving a first signal from a first region of a
neural signaling pathway of a patient's brain, determining a pacing
signal that when applied to a second region of the brain induces
the neurons in the second region of the brain to generate a second
signal substantially similar to the first signal, and applying the
pacing signal to the second region of the brain, thereby
establishing a neural signaling pathway between the first and
second regions and improving a cognitive function.
In certain embodiments, the method further comprises determining an
alertness level of the patient. In certain embodiments, the method
further comprises determining the therapy or response based on the
alertness level. In certain embodiments, the patient exhibits at
least two alertness levels. In certain embodiments, improving a
cognitive function comprises improving at least two different
cognitive functions that correspond to the at least two alertness
levels.
In certain embodiments, the alertness level is determined based on
the set of inputs. In certain embodiments, the alertness level is
determined based on hippocampal theta rhythm. In certain
embodiments, the alertness level is high and improving a cognitive
function comprises inducing neurons in the second region of the
patient's brain to induce hippocampal theta rhythm. In certain
embodiments, the alertness level is low and improving a cognitive
function includes inducing the neurons in the second region of the
patient's brain to induce hippocampal sharp waves.
In certain embodiments, the alertness level is determined based on
a state of consciousness of the patient including awake and/or
alert and/or sleep and/or unconsciousness. In certain embodiments,
the alertness level is determined based on whether the patient's
brain is processing information or consolidating information. In
certain embodiments, the alertness level is user configurable. In
certain embodiments, the alertness level is determined by a
user.
In certain embodiments, the first and/or second regions include
portions of the patient's brain that enable memory functions and
are selected based on the alertness level.
In certain embodiments, improving a cognitive function includes
applying an electrical signal and/or a chemical signal to neurons
in the second region of the patient's brain to induce a hippocampal
theta rhythm. In certain embodiments, the theta rhythm is induced
by stimulating activating neurons and/or inhibiting neurons in the
second region. In certain embodiments, the neurons in the second
region are located the nucleus pontis oralis and/or median raphe
nucleus.
In certain embodiments, improving a cognitive function includes
delivering at an electrical signal and/or a chemical signal to
neurons in the second region of the patient's brain to induce
hippocampal sharp waves. In certain embodiments, the hippocampal
sharp waves are induced by stimulating activating neurons and/or
inhibiting neurons in the second region.
In certain embodiments, receiving a first signal includes measuring
an electrical signal and/or a chemical signal. In certain
embodiments, the electrical signal includes a theta signal and/or a
gamma signal. In certain embodiments, improving a cognitive
function includes applying an electrical signal and/or chemical
signal to induce neurons in the second region of the patient's
brain to generate a signal that is substantially similar to the at
least one of the set of inputs.
In certain embodiments, the cognitive function includes memory.
In certain embodiments, the neural signaling pathway include
neurons connecting at least two of CA1, CA2, CA3, Dentate Gyrus,
Entorhinal Cortex, Hilus, and subiculum.
In certain embodiments, the neural signaling pathway includes the
Perforant Path, Schaffer Collateral Pathway, and Associational
Commissural Pathway.
BRIEF DESCRIPTION OF THE DRAWINGS
The following figures depict certain illustrative embodiments of
the invention in which like reference numerals refer to like
elements. These depicted embodiments may not be drawn to scale and
are to be understood as illustrative of the invention and not as
limiting in any way.
FIGS. 1A and 1B depict views of the brain and the hippocampus
regions.
FIGS. 2A and 2B depict a therapy system, according to an
illustrative embodiment of the invention.
FIGS. 3A and 3B depict a therapy system, according to illustrative
embodiment of the invention.
FIGS. 4A-5 depict schemes for pacing one or more neural clusters in
the brain according to an illustrative embodiment of the
invention.
FIGS. 6A-6D depict schemes for combining pacing signals and neural
firing patterns of one or more neurons.
FIG. 7 depicts an illustrative mode-based scheme for delivering
therapy.
FIGS. 8A-8D depict the degradation of implantable elements in the
brain.
FIGS. 9A-9D depict a therapy system, according to an illustrative
embodiment of the invention.
FIG. 10 depicts recording electrodes, according to an illustrative
embodiment of the invention.
DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS
As will be seen from the following description, in some aspects,
the invention relates to systems and methods for providing
cognitive therapy through stimulation of activating and inhibiting
neurons in the brain, thereby modulating neural firing rhythms.
The present invention may be embodied in various forms to analyze
and treat disorders in cognitive function. Cognitive function
includes attention, executive function, reaction time, learning
information processing, conceptualization, problem solving, verbal
fluency and memory (e.g., memory consolidation, short term memory,
working memory, long term memory, declarative memory or procedural
memory). Impairment in a cognitive function treated by the methods
described herein can be an impairment in attention, which is the
capacity or process of selecting out of the totality of available
sensory or affective stimuli, those stimuli that are most
appropriate or desirable for focus at a given time (Kinchla, R. A.,
et al., Annu. Rev. Psychol. 43:711-742 (1992)). A disorder in a
cognitive process can result in an impairment in executive
function, which are neuropsychological functions such as decision
making, planning, initiative, assigning priority, sequencing, motor
control, emotional regulation, inhibition, problem solving,
planning, impulse control, establishing goals, monitoring results
of action and self-correcting (Elliott, R., Br. Med. Bull. 65:49-59
(2003)). The cognitive impairment can be an impairment in
alertness, wakefulness, arousal, vigilance, and reaction time
information processing, conceptualization, problem solving and/or
verbal fluency. Cognitive disorders include, for example without
limitation, Alzheimer's disease, MCI (mild cognitive impairment),
dementia, amnesia and memory disorders as can occur after injury,
trauma, stroke, cranial irradiation, and in the context of genetic,
congenital, infectious, autoimmune, toxic (drugs and alcohol),
nutritional (vitamin deficiencies) metabolic, inflammatory,
neurodegenerative neoplastic or idiopathic processes involving the
brain. Some additional specific disorders where the therapy of the
invention may be useful include: amnestic syndromes,
Werkicke-Korsakoff and Korsakoff syndromes, Herpes encephalitis,
severe hypoxia, vascular disorders, head injury, transient global
amnesia, global amnesia epileptic amnesia, cerebral palsy, autism,
mental retardation and attention deficit and hyperactivity
disorders.
The application provides methods to improve cognitive function. The
cognitive function can be assessed or determined by established
techniques known to one skilled in the art. For example, memory can
be assessed before, concomitantly with or after treatment of the
individual by one or more well established tests known to one of
skill in the art. Such tests include the Rey Auditory Verbal
Learning Test (RAVLT); Cambridge Neuropsychological Test Automated
Battery (CANTAB); a Children's Memory Scale (CMS); a Contextual
Memory Test; a Continuous Recognition Memory Test (CMRT); a Denman
Neuropsychology Memory Scale; a Fuld Object Memory Evaluation
(FOME); a Graham-Kendall Memory for Designs Test; a Guild Memory
Test; a Learning and Memory Battery (LAMB); a Memory Assessment
Clinic Self-Rating Scale (MAC-S); a Memory Assessment Scales (MAS);
a Randt Memory Test; a Recognition Memory Test (RMT); a Rivermead
Behavioral Memory Test; a Russell's Version of the Wechsler Memory
Scale (RWMS); a Test of Memory and Learning (TOMAL); a Vermont
Memory Scale (VMS); a Wechsler Memory Scale; a Wide Range
Assessment of Memory and Learning (WRAML); First-Last Name
Association (Youngjohn J. R., et al., Archives of Clinical
Neuropsychology 6:287-300 (1991)); Name-Face Association; Wechsler
Memory Scale-Revised (Wechsler, D., Wechsler Memory Scale-Revised
Manual, NY, N.Y., The Psychological Corp. (1987)); California
Verbal Learning Test-Second Edition (Delis, D. C., et al., The
Californian Verbal Learning Test, Second Edition, Adult Version,
Manual, San Antonio, Tex.: The Psychological Corporation (2000));
Facial Recognition (delayed non-matching to sample); Cognitive Drug
Research (CDR) Computerized Assessment Battery-Wesnes; Buschke's
Selective Reminder Test (Buschke, H., et al., Neurology 24:
1019-1025 (1974)); Telephone Dialing Test; Brief Visuospatial
Memory Test-Revised; and Test of Everyday Attention (Perry, R. J.,
et al., Neuropsychologia 38: 252-271 (2000)).
An improvement in cognitive function may be determined by an
improvement in performance in a cognitive test, as described above.
Alternatively, an improvement in cognitive function may also be
established in a patient as a decrease in the decline of cognitive
function, for example in a disorder characterized by a continuing
decrease in cognitive function, e.g., Alzheimer's disease.
The patient receiving this treatment is any animal in need,
including primates, in particular humans, and other mammals such as
equines, cattle, swine and sheep; and poultry and pets in
general.
The stimulation of neurons is controlled through a feedback process
whereby neuron firing rhythms are altered based on naturally
occurring electrical and chemical activity in the brain. Neurons in
specific regions of the brain may be targeted in order to establish
neural signaling pathways and establish communication between these
regions.
To provide an overall understanding of the invention, certain
illustrative embodiments will now be described, including the
cognitive therapy scheme and constituent components thereof.
However, it will be understood by one of ordinary skill in the art
that the methods and systems described herein may be adapted and
modified as is appropriate for the application being addressed and
that the systems and methods described herein may be employed in
other suitable applications, and that such other additions and
modifications will not depart from the scope hereof.
FIG. 1 shows a human brain 100 in which the hippocampus is a part
of the brain that is located in the medial temporal lobe. The
hippocampus forms part of the limbic system. Typical human brains
have two hippocampi 102a and 102b, one in each side of the brain.
The role of the hippocampus is in the formation of new memories
about episodic events. The hippocampus is generally part of a
larger medial temporal lobe memory system that is also responsible
for general declarative memory (memories that be verbalized such as
memory for facts). The hippocampus is also responsible for storing
and processing spatial information. Studies in rats have shown that
neurons in the hippocampus have spatial firing fields. As a result,
the hippocampus is required for simple spatial memory tasks (e.g.,
finding the way back to a hidden goal). The hippocampus is also
shown to modulate emotional reactions. Certain experiments have
shown that mild stimulation of the hippocampus have an alerting
reaction characterized with cortical de-synchronization,
respiratory acceleration, and heart rate increase.
Around the hippocampus, there is septal nucleus (102c) and medial
septum (102d). Medial septum is typically recognized as the
pacemaker of the hippocampus. Furthermore, the hippocampus curls
around the fornix (102e) and fimbria (102f), the thalamus (102g),
raphe nuclei (102h), Amygdala (102i), supramammillary nucleus
(102j), and neocortex (102k).
FIG. 2 depicts the anatomy of the hippocampus 102 and information
flow through the various regions in the hippocampus. The
hippocampal region generally refers to the dentate gyrus 110, the
Cornu Ammonis fields CA1 104, CA2 106, CA3 108 (and CA4, frequently
called the hilus and considered part of the dentate gyrus 110), and
the subiculum.
Information flow through the hippocampus 102 proceeds from one
region to another along neural signaling pathways. In particular,
information flow proceeds from the dentate gyrus 110 to CA3 108 to
CA1 104 to the subiculum, with additional input information at each
stage and outputs at each of the two final stages. CA2 104
typically represents a small portion of the hippocampus 102 and, in
general, is resistant to conditions that usually cause large
amounts of cellular damage, such as epilepsy.
The perforant path 112, which brings information primarily from
entorhinal cortex (but also perirhinal cortex, among others), is
generally considered a main source of input to the hippocampus 102.
Layer II of the entorhinal cortex (EC) brings input to the dentate
gyrus and field CA3, while EC layer III brings input to field CA1
and the subiculum. The main output pathways of the hippocampus are
the cingulum bundle and the fimbria/fornix, which arise from field
CA1 104 and the subiculum.
Perforant path 112 input from EC layer II enters the dentate gyrus
110 and is relayed to region CA3 108 (and to mossy cells 120,
located in the hilus of the dentate gyrus 110, which then send
information to distant portions of the dentate gyrus 110 where the
cycle is repeated). Region CA3 108 combines this input with signals
from EC layer II and sends extensive connections within the region
and also sends connections to region CA1 104 through a set of
fibers called the Schaffer collaterals 114. Region CA1 104 receives
input from the CA3 108 subfield, EC layer III and the nucleus
reuniens of the thalamus (which project only to the terminal apical
dendritic tufts in the stratum lacunosum-moleculare). In turn, CA1
104 projects to the subiculum as well as sending information along
the aforementioned output paths of the hippocampus 102. The
subiculum is typically the final stage in the pathway, combining
information from the CA1 104 projection and EC layer III to also
send information along the output pathways of the hippocampus.
The hippocampus also receives a number of subcortical inputs. In
Macaca fascicularis 120, these inputs include at least one of the
amygdala (specifically the anterior amygdaloid area, the
basolateral nucleus, and the periamygdaloid cortex), the medial
septum and the diagonal band of Broca, the claustrum, the
substantia innominata and the basal nucleus of Meynert, the
thalamus (including the anterior nuclear complex, the laterodorsal
nucleus, the paraventricular and parataenial nuclei, the nucleus
reuniens, and the nucleus centralis medialis), the lateral preoptic
and lateral hypothalamic areas, the supramammillary and
retromammillary regions, the ventral tegmental area, the tegmental
reticular fields, the raphe nuclei (the nucleus centralis superior
and the dorsal raphe nucleus), the nucleus reticularis tegementi
pontis, the central gray, the dorsal tegmental nucleus, and the
locus coeruleus.
Memory formation generally has two steps including information
processing and information consolidation. During information
processing, the information is temporarily stored in the CA3 108.
During information consolidation, the information from the CA3 108
is transferred to the CA1 104 and subsequently onto the cortex.
The various regions in the brain (including the hippocampus) are
composed of electrically active and electrically excitable cells
called neurons. Neurons transfer information along the neural
signaling pathway through synaptic transmission, whereby neurons
communicate via chemical and electrical signals (e.g., action
potentials) that are transferred from one neuron to another.
Typically each neuron follows a firing pattern whereby the neuron
generates an electrical or chemical signal in a train of spikes
(e.g., action potentials) at regular intervals. A group of neurons
in close proximity to each other may fire independently but still
demonstrate an overall rhythm. This overall rhythm may exhibit
certain patterns that may be associated with certain behavior.
As an example, the overall rhythm of hippocampal neurons may
exhibit a theta rhythm having a frequency from about 4 Hz to about
8 Hz. The theta rhythm has been demonstrated as being an important
requirement during the information processing stage of memory
formation and may be manifested during some short term memory
tasks. Theta rhythm is associated with gamma oscillations having a
frequency of about 40 Hz to about 100 Hz recorded in the hilus
and/or the CA1 104. Theta rhythm is also associated with sodium
spike activities.
As another example, the overall rhythm of hippocampal neurons may
exhibit sharp waves having a duration of about 40 to about 120 msec
and a frequency of about 200 Hz. These sharp waves can be recorded
in CA1 and/or CA3.
Damage to the hippocampus usually results in profound difficulties
in forming new memories as well as affecting memories prior to
damage. Disorientation and memory recall problems therefore appear
as early symptoms in disorders affecting the hippocampus, such as
Alzheimer's disease.
Electrical and/or chemical stimulation of regions or neural
clusters in the hippocampus provides a therapy for improving memory
formation. In particular, electrical and/or chemical stimulation of
the hippocampal neurons can affect their firing patterns. For
example, electrical stimulation has been demonstrated to disrupt
theta activity, which in turn affects memory. Superimposing an
artificial stimulating rhythm to the hippocampus improves memory
performance in animals whose memory was partially impaired.
Alternatively, chemical stimulation may be provided as therapy for
improving cognitive function. Any number of drugs may be
administered as a chemical stimulation including, but not limited
to, an anesthetic, a GABA agonist, a GABA antagonist, a glutamate
antagonist, a glutamate agonist, a degrading enzyme, a reputake
blocker, and a dopamine antagonist. An activating chemical may be
used and includes any chemical that causes an increase in the
discharge rate of the projection nerve cells from a region. An
example (for projection neurons which receive glutamatergic
excitation and GABA inhibition) would be an agonist of the
transmitter substance glutamate (facilitating the excitation) or a
GABA antagonist (blocking the inhibition). Conversely, a blocking
chemical may be used and includes any chemical that inhibits the
projection neurons thereby causing a decrease in the discharge rate
of the projection nerve cells from a region. An example would be a
glutamate antagonist (blocks excitatory input to the projection
nerve cells) or a GABA agonist (enhances inhibition of the
projection neurons).
FIGS. 2A and 2B depict a therapy system 200 according to an
illustrative embodiment of the invention. In particular, the
therapy system 202 includes a pair of implantable elements 206 and
208 and control circuitry 204 located inside a casing 202. The
casing placed on the skull 212 and underneath the scalp 214. A hole
through the top portion of the skull allows the implantable
elements 206 and 208 to be inserted into one or more regions of the
brain. The casing 202 may be placed by rolling back the scalp,
drilling a hole in the skull, cutting open the dura and other
membranes, and using stereotactic frame or intraoperative MRI. The
implantable elements 206 and 208 may be linked to the casing 202 by
flexible interconnects. The interconnects are carefully lowered
into the skull and the csing 202 is inserted in the drilled hole.
Each of the implantable elements 206 and 208 are inserted in
regions 210a and 210b of the brain. During operation, the
implantable elements 206 and 208 record and/or stimulate neurons in
these regions.
The implantable elements 206 and 208 may include electrodes to
measure and record electrical signals. The electrodes may also be
capable of generating electrical fields and thereby delivering
electrical signals to a particular region of the brain. The
implantable elements are generally narrow and include a pointed tip
for penetrating through the brain. In certain embodiments, the
electrodes include conductive channels to generate an electric
field in the vicinity of the electrode. These conductive channels
may be arranged in any suitable pattern along the electrode. The
implantable elements 206 and 208 may also include chemical sensors
to measure and record chemical concentrations, e.g., calcium and/or
acetylcholine and/or neurotransmitters. The implantable elements
206 and 208 may include catheters and valves to deliver and control
the release of chemical compounds into the brain. In certain
embodiments, the implantable elements 206 and 208 may include
electrical and chemical sensors and stimulators along with other
components including light sources and electronic circuitry. One
suitable type of implantable device is shown in U.S. Pat. No.
7,010,356, "Multichannel Electrode and Methods of Using Same," the
entire contents of which is herein incorporated by reference. The
implantable elements and circuitry may include MEMS based devices
and nanostructures to allow for specific placement.
The casing may include a transcranial casing having suitable
properties for implantation on the surface of the skull underneath
the scalp.
In certain embodiments, the control circuitry includes electronic
components for receiving, processing and generating signals to
stimulate neural clusters. FIG. 2B is a block diagram depicting a
therapy system 200 having control circuitry including a processor
220, memory/storage 222, an analog-to-digital converter 224, and a
signal generator 226. The control circuitry is connected to a valve
228 that controls the flow of chemical compounds from a reservoir
230 to the implantable element 208. The various components in the
system 200 are powered by power supply 234.
The processor 220 may include a single microprocessor or a
plurality of microprocessors for configuring control circuitry as a
multi-processor system. The memory 222 may include a main memory
and a read only memory. The memory 222 may also include the mass
storage device such as flash drives. The main memory 222 also
includes dynamic random access memory (DRAM) and high-speed cache
memory. In operation, the main memory 222 stores at least portions
of instructions and data for execution by the processor 220.
In certain embodiments, the implantable devices 206 include sensors
capable of detecting electrical activity and/or chemical
concentrations in the brain and outputting an analog electrical
signal that is representative of the activity or concentration. The
system 200 includes an analog-to-digital converter 224 for
receiving the measured analog signals from the implantable elements
206 and converting these signals to digital form for the processor
220.
The system 200 includes a signal generator 226 having circuitry
that is capable of generating an electrical pacing signal based on
a digital command from the processor 220. The pacing signal is sent
to the implantable element 208 which delivers the signal to the
brain.
The implantable element 208 may further include a catheter 232 for
delivering chemical compounds to regions of the brain. These
catheters may be connected to a chemical compound reservoir 230 via
a programmable valve 228. The processor 220 may send control
signals to open or close the valve 228 and thereby control the flow
of the chemical compounds from the reservoir 230 to the brain via
catheter 232.
Regions 210a and 210b may be part of the hippocampus and a
cognitive function such as memory recall may be facilitated by
neural communication between regions 210a and 210b. In certain
embodiments, the regions 210a and/or 210b may include the medial
septum, basalis nucleus, supramammillary nucleus, posterior nucleus
hypothalamus, raphe nucleus, fornix, fimbria and neocortex. In
particular, information may flow from region 210a to 210b. However,
the neural signaling pathway between regions 210a and 210b may be
damaged (e.g., due to degeneration of one or more neurons), causing
diminished cognitive function. Cognitive functions such as memory
recall are correlated with theta activity. The implantable element
206 may be used to record theta activity in region 210a. The
control circuitry 216 may then develop a therapy that may include
generating a pacing signal to be applied to region 210b. The pacing
signal delivered by the implantable element 208 induces theta
activity in region 210b that may be similar to the theta activity
in region 210a. In certain embodiments, at least one of elements
206 and 208 or any additional elements may be used measure other
parameters to adjust the pacing signal.
The power supply 234 may include single-charge type energy sources
or rechargeable energy sources. Single-charge energy sources are
typically disposed after the energy stored within the single-charge
energy source is drained. In certain embodiments, single-charge
energy sources include disposable alkaline or mercury based
batteries. In certain embodiments, the power supply 234 includes
rechargeable energy sources. The rechargeable batteries may include
one or more Lithium ion batteries. The rechargeable batteries may
also include at least one of a lead acid, a nickel metal hydride
and a nickel cadmium battery. In other embodiments, the
rechargeable energy source includes other soft rechargeable
batteries. The rechargeable energy source may also include other
capacitive storage type batteries.
FIG. 3A depicts a therapy system 300 for providing therapy to a
neural signaling pathway 322. The neural signaling pathway 322
includes three neural cluster regions 310a, 310b and 310c. The
signal pathway may begin at cluster 310a and end at cluster 310c.
The three implantable elements 306, 307 and 308 are positioned near
each of the three neural clusters 310a, 310b and 310c,
respectively. The system includes casing 302 that may be similar to
casing 202 for housing the control circuitry. In particular, casing
302 houses control circuitry 316, recording circuitry 318 for
recording electrical signals from the neural cluster 310a through
implantable element 306, and pacing circuitry 320 for stimulating
the neural cluster 310c through implantable element 308.
The implantable element 307 includes a catheter for delivering
chemical substances to neural cluster 310b. The control circuitry
316 may also include a chemical reservoir for providing chemical
substances to the catheter 307. Implantable element 307 may also
include electrical and/or chemical sensors capable of measuring
chemical and electrical activity in neural cluster 310b.
During operation, a measurement may be taken by element 306 to
determine if the neural pathway 322 is activated. The control
circuitry 316 determines if the pathway 322 is activated by
measuring the electrical activity in cluster 310a. If the pathway
322 is not yet active, the control circuitry 316 applies a signal
(such as a voltage signal) at cluster 310a using implantable
element 306. The control circuitry 316 then determines if the
pathway 322 is activated at cluster 310b. If the pathway 322 is not
active in cluster 310b, the control circuitry delivers a chemical
compound to the cluster 310b to induce the neurons to generate an
electric field. The element 308 measures the electrical and/or
chemical activity in cluster 310c to determine if the signal
generated at either regions 310a or 310b has reached region
310c.
Certain types of neurons in the region activate theta rhythms and
certain types of neurons in the region inhibit the theta rhythm. In
certain embodiments, the implantable elements may be configured to
deliver a pacing signal to selectively stimulate each of the
activating and inhibiting neurons to induce a desired theta
rhythm.
FIG. 3B depicts an exemplary implantable element 324, according to
an illustrative embodiment of the invention for inducing a desired
theta rhythm by stimulating activating and inhibiting neurons. In
particular, element 324 is a directional electrode having one or
more conductive channels facing 180 degrees away from another one
or more conductive channels. The nucleus pontis oralis and the
median raphe nucleues are neuron clusters in the hippocampus that
activate and inhibit, respectively, theta activity. The electrode
324 is positioned such that one set of conductive channel faces the
nucleus pontis oralis and the other set of conductive channels
faces the median raphe nucleus.
In certain embodiments, the electrode 324 may deliver a stimulating
or pacing signal to at least one of each of the set of conductive
channels. Such an electrode is advantageous because it allows the
operations of activation and inhibition to be performed together
and avoid conflicts in theta activity generation arising from
activating both sets of nuclei or inhibiting both sets of nuclei
simultaneously.
As discussed thus far, one or more regions may be stimulated based
on measurements made from one or more regions. FIGS. 4A-4C depict
various schemes for providing therapy whereby one or more regions
(or clusters) are paced.
FIG. 4A is a schematic representation for a scheme to provide
therapy to a neural signaling pathway 402. The pathway 402 as shown
includes five neural clusters whereby information flows from neural
cluster 404a to 404e. It may be desirable to modify the behavior of
the pathway 402 to cause a certain behavior associated with a
cognitive function. Therefore, there may be a need to record
signals from one or more clusters in the pathway 402 and pace one
or more selected clusters. In the illustrated embodiment,
electrical and/or chemical signals from each of the neural clusters
404a-404e are recorded by the control circuitry 406. The control
circuitry 406 may be similar to control circuitry 202 (FIG. 2B).
The control circuitry 406 records signals from each of the clusters
404a-404e and determines a suitable therapy including a pacing
signal. The pacing signal may be applied to one or more of the
clusters. In the illustrated embodiment, the pacing signal is
applied to cluster 404c.
The selection of a suitable neural cluster 404c for pacing may
depend on convenience to implant, convenience to modify electrical
and/or chemical activity in that region, and on resulting side
effects. In certain embodiments, during memory formation, certain
pathways carrying processing information and certain regions where
selective activation occurs may be less suited for pacing and the
pacing signal may be applied elsewhere. As an example, during
information processing, the Entorhinal Cortex is active, but its
activity is processing the data and transporting the data into the
hippocampus. There is then a risk that processed information may be
lost if the Entorhinal Cortex is paced. As another example, during
information processing, the CA3 is selectively activated as the
processed information is stored into a selected location. There is
then a risk that the storing process may be disrupted if the entire
CA3 is paced/stimulated.
In other embodiments, the pacing location may be selected close to
the root of the signal pathway. Selecting the pacing location close
to the root of the pathway allows for simpler pacing that can
activate the entire pathway. However, roots may be located in
sensitive regions of the brain such as the brainstem and
consequently implantation of electrodes and other implantable
elements becomes more difficult. Such a choice of pacing location
may result in unwanted stimulation of neighboring clusters not
along the pathway. Moreover, in the event that one or more clusters
along the pathway are damaged, pacing the cluster near the root of
the pathway may not be useful since there might be a break along
the pathway near the damaged cluster to hinder the flow of
information.
In certain embodiments, the pacing location may be selected at a
location of a missing or damaged neural cluster. FIG. 4B depicts
such a configuration whereby the control circuitry 406 delivers a
pacing signal to cluster 404c. In particular, the control circuitry
406 may record the activity at cluster 404b and generate a pacing
signal that, when applied to cluster 404c induces the neurons to
generate activity similar to that at cluster 404b. Such a scheme
may complete a broken pathway 402.
In other embodiments, the pacing location may be selected close to
the end of the signal pathway. In such embodiments, clusters 404d
and 404e may be directly paced to bypass damaged cluster 404c based
on the activity at cluster 404b. Bypassing the damaged cluster 404c
may be necessary if the damage is so extensive that a response
cannot be elicited regardless of increased stimulation.
Alternatively, as depicted in FIG. 4C, cluster 404c may be
functioning, but it might be in close proximity to a cluster 408
that may be a sensitive cluster not along the pathway 402. In such
cases, pacing at cluster 404c may influence cluster 408 and thereby
cause undesirable side effects. In such cases, the end cluster 404e
may be paced based on the activity measured at the first cluster
404a, thereby forming an artificial neural pathway that bypasses
the pathway 402.
FIGS. 5-6D depict various pacing schemes in addition to those
depicted in FIGS. 4A-4C that are applied to one or more regions of
the brain. In particular, FIG. 5 is a control block diagram
depicting a scheme 500 for pacing and providing therapy, according
to an illustrative embodiment of the invention. In particular, FIG.
5 depicts a neural signaling pathway including regions or neural
clusters 502a, 502b and 502c. Information may flow from node 502a
to 502c. Implantable elements 506 and 508 are inserted into regions
502c and 502a, respectively. The implantable elements 506 and 508
are connected to control circuitry 510.
During operation, according to scheme 500, the control circuitry
applies a pacing signal in region 502a.
The pacing signal applied at regions 502a is modulated based on a
recorded feedback signal measured at region 502c, which may be at
the end portion of the pathway 504.
The feedback signals have a smaller amplitude than the pacing
signal and provide for a measure of accuracy and effectiveness of
the pacing scheme. In particular, pacing effectiveness may be
measured by evaluating memory formation to determine if memory is
correctly being processed and stored. Electrical activity such as
theta rhythm and/or gamma rhythm are quantifiable measures that are
used to determine the effectiveness of the pacing scheme. In
certain embodiments, chemical concentrations are also suitable
measures to determine the effectiveness of a pacing scheme.
Behavioral memory assessments, as previously described, may also be
used to determine pacing effectiveness. The feedback signal may be
any measure that is related to the activity being paced. In certain
embodiments, the feedback signal and the activity being paced may
follow a one-to-one mapping. The feedback signal may be any signal
that changes in response to the application of the pacing signal.
In certain embodiments, time latency between a change in the
feedback signal in response to a change in the pacing signal is
low. The feedback signal may also include any signal that can be
measured in a consistent manner from patient to patient and from
time to time.
The feedback signal is depicted as being measured from region 502c.
However, the feedback signal may be measured in other locations
without departing from the scope of the invention. In particular,
the feedback signal may be measured in a region having low levels
of noise, or substantially constant levels of noise. The feedback
signal may be measured in a location that is accessible and can
accommodate an implantable element. In certain embodiments, the
region has a nucleus from about 2 mm to about 4 mm.
The feedback signal may be measured at a location that the pacing
signal can be measured. In certain embodiments, the feedback signal
is placed away from a location that is currently being paced.
FIGS. 6A-6D are control block diagrams representing different
pacing schemes, some measuring a feedback signal. In particular,
FIG. 6A depicts a scheme 600 whereby a therapy system 602 (similar
to system 200 of FIGS. 2A and 2B including implantable electrodes
and control circuitry) applies a pacing signal to one or more
neurons 604 to cause the neuron 604 to alter its firing patterns.
As an example, the system 602 may apply a high frequency pulse
waveform to a region in the brain to stimulate activating or
inhibiting neurons thereby controlling the firing pattern in that
region.
FIG. 6B depicts a scheme 620 whereby the pacing signal generated by
system 602 is superimposed on a normal firing pattern of one or
more neurons 604. In another embodiment, as depicted in scheme 630
in FIG. 6C, the system 602 alters the neuron firing patterns and
then superimposes the altered firing pattern on the pacing signal.
FIG. 6D depicts a scheme 640 that includes the effect of a feedback
measurement made by the system 602.
In certain embodiments, in addition to measuring pacing
effectiveness and providing real-time feedback to the therapy
system, one or more signals may be recorded in the brain to
determine a suitable type or mode of therapy. For example, as noted
earlier, memory formation occurs in two steps--information
processing and information consolidation. During each of these
steps, neuronal activity tends to be different and consequently the
brain may require different types of therapy. One or more signals
from the brain may be used to determine whether it is currently
processing information or consolidating information. As an example,
if the brain is currently processing information, the therapy
system may induce a hippocampal theta rhythm and if the brain is
currently consolidating information, the therapy system may switch
modes and induce sharp waves.
Information processing naturally tends to occur during wake hours
and/or other alert times, especially when a patient is
concentrating. Information consolidation naturally tends to occur
during sleep hours and/or other inactive times including when the
patient is awake but doing routine tasks. When a patient is alert,
theta oscillations and sodium spike activity are involved in the
continuous recording of activity in the hippocampus. The amount of
neurotransmitters in the hippocampus decreases, however, during
slow wave sleep, awake immobility, drinking, eating, face washing,
and grooming. Decreased release of neurotransmitters in turn
inhibits the steady potassium current necessary to maintain
sustained sodium spike activity. This results in the conversion of
hippocampal and cortical cells to a bursting firing mode,
characterized by the appearance of sharp waves. Increased calcium
is released as a result of the burst in firing, which is
hypothesized to play a role in memory consolidation. It then
follows that methods for specifically improving information
processing should be performed when a patient is highly alert,
while methods for specifically improving information consolidation
should be performed when a patient is not highly alert,
specifically when the hippocampal cells are in bursting firing
mode.
According to the present application, different alertness levels of
a patient may be determined. Alertness levels can be inferred from
other brain activities that have been commonly analyzed via
electroencephalography or EEG signals. For example, as a person
falls asleep or looses concentration, brain activity is modulated,
representing different depths and phases of consciousness and
attentiveness. A typical persons transitions through different
levels of brain activity over time, starting at a first sleep state
known as slow wave sleep or SWS. SWS has low frequency high power
EEG activity. The sleep may lighten into so-called intermediate
sleep states. Another sleep state known as rapid eye movement sleep
is characterized by a lower power EEG activity. An alertness level
may be described as any distinguishable sleep or wakefulness that
is representative of behavioral, physical or signal
characteristics. Awake states may actually be part of the sleep
state, i.e., part of a low alertness level, and the awake states
can be characterized by vigilance into attentiveness or levels of
alertness.
The alertness level of a patient can be measured from at least one
of alpha, beta and theta activity in the brain. The alertness level
may also be set by a patient or another user based on whether or
not the patient is alert in one or more of their senses including
sight, hearing, smell, touch and taste.
In certain embodiments, the therapy system has at least two
operating modes for two steps in memory formation and these modes
correspond to the alertness level of the patient. In some
embodiments, a high alertness level is characterized by hippocampal
and/or cortical theta rhythm, while a low alertness level is
characterized by the lack of hippocampal and/or cortical theta
rhythm.
FIG. 7 is a block diagram depicting a mode-based therapy system
700. The system 700 includes a user interface 702 capable of
receiving an alertness level from a user and an alertness
monitoring module 706 including an implantable element 708 and
control circuitry for measuring the alertness of the patient. The
system 700 further includes control circuitry 704 that is
configured to determine a mode of therapy based on the alertness
level determined by the alertness monitoring module 706 and the
user configured alertness level from the user interface 702. The
user interface 702 may include an option to either manually or
automatically determine the alertness of the patient.
The control circuitry 704, after determining the mode of therapy,
applies the corresponding therapy scheme 710 or 712 (e.g., pacing
signal) to a region of the brain. In the illustrated embodiment,
each a the therapy schemes 710 and 712 include two implantable
elements 709, 711, 713, and 715 for recording 714 and 716
stimulating 718 and 720 electrical and/or chemical activity in the
brain.
In certain embodiments the therapy scheme 710 is applied during the
information processing stage of memory formation and includes the
measurement of neuronal activities typically relevant to
information processing including theta rhythm, gamma activity and
sodium concentration. The therapy scheme 712 may be applied during
the information consolidation stage of memory formation and
includes the measurement of neuronal activities such as bursting
activity and calcium concentrations.
As noted earlier, the therapy systems include implantable elements
such as electrodes and chemical sensors for measuring activity and
applying signals to one or more regions in the brain. These therapy
systems also include control circuitry configured to automatically
provide therapy for extended periods of time. However, typical
implantable elements, used to measure electrical and chemical
activity in the brain, tend to fail or migrate after a certain
period of time. This may be due, at least in part, to the fact that
these implantable elements such as electrodes used to record single
neuron activity typically have a high impedance and a small contact
surface.
FIGS. 8A-8D depict typical problems encountered when recording
neuronal signals. FIG. 8A depicts an electrode 800 having a
recording contact 802 and a conductive track 803. The electrode 800
may be configured to record neuronal activity occurring within a
volume 804 around the contact 802. The electrode may be capable of
recording electrical activity from a neuron 805 within the volume
804.
However, in time, as depicted in FIG. 8B, Glial scarring tissue 808
covers the contact surface 802, thereby preventing the conductors
in the electrode from interfacing with the extracellular fluid. As
a result, the electrode may no longer be able to measure activity
from the neuron 805.
As shown in FIG. 8C, the contact surface 802 of the electrode may
also suffer from erosion thereby decreasing the recording volume
804. As a result, the neuron 805 may fall outside of the eroded
recording volume 804 and the electrode may no longer be able to
record activity from the neuron 805.
The electrode may migrate and, as depicted in FIG. 8D, even small
migrations can cause the neuron 805 to fall outside of the volume
804. As a result, the electrode may no longer be able to record
activity from neuron 805.
In certain embodiments, the electrodes used to measure local field
potential, which may be a summation of activities from multiple
neurons in close proximity, have larger contact surfaces than the
electrodes used to measure single neuron activity. These electrodes
(long-term electrode) tend to last longer than the electrodes
(short-term electrodes) used to measure single neuron activity.
FIGS. 9A and 9B depict a system method for combining the
specificity of a short term electrode with the longevity and
spatial independence of a long term electrode. In particular, FIG.
9A depicts a system 900 having an electrode 902 for recording
single neuron activity (short term electrode) and an electrode 904
for recording local field potential (long term electrode).
The electrodes 902 and 904 are connected to an implantable pulse
generator (IPG) 906 that includes a processor 908 and a pulse
generator 910. The IPG 906 may be similar to the control circuitry
202 of FIG. 2. The pulse generator 910 delivers a pacing signals to
the stimulation electrodes 912. The stimulation electrodes 912
provide natural activity information at the stimulation site to the
processor 908.
In certain embodiments, the electrodes 902 are implanted in a
location where theta activity is generated, such as the
hippocampus. The electrode 904 may be implanted in a location where
a component of the local field potential is the theta activity
information. The stimulation electrode 912 may be implanted in a
location where theta activity can be elicited, such as the fornix
or the septal region. The IPG 906 may be implanted in the body
close to the electrodes.
During operation, the system 900 initially uses the measurements
from electrodes 902 and 904 to train an inference engine. The
inference engine may correlate the long term signal to the short
term signal. In the event that the short term electrode 902 fails,
the system 900, with the aid of the inference engine in the
processor 908, infers a feedback signal from the signal obtained
from long-term electrode 904. This feedback signal helps the
processor 908 to determine an appropriate pacing signal.
As depicted in FIGS. 9B-9D, the system 900 may operate in three
modes including a training mode (FIG. 9B), a learning mode (FIG.
9C) and a regular mode (FIG. 9D). During training mode, the
processor 908 receives input signals from short-term electrode 902
and long-term electrode 904 and uses each of the inputs to train an
inference engine.
In certain embodiments, more than one long-term electrode is used.
The inference engine may include circuitry configured to run an
artificial intelligent scheme that teaches itself to interpret
long-term data. For instance, the circuitry may include an
artificial neural network or HMM. In certain embodiments, the
scheme includes a signal source localization scheme. The inference
engine may further include circuitry for measuring the life of a
short term electrode. In certain embodiments, the inference engine
may include circuitry for measuring impedance and/or
signal-to-noise ratio of the electrode. The inference engine may
have a module that regularly checks whether the short term
electrode is still working. The module may be configured to check
the impedance level and once the impedance crosses a certain
threshold, the short term electrode may be deemed to have failed
and the inference engine switches from training to functioning.
The processor 908 generates a pacing signal based on the input
signals from the short-term electrode 902 and from an archive of
one or more memory exercises performed by the patient. During the
learning mode (FIG. 9C), the patient performs a series of memory
exercises under supervision. During this mode, the stimulation
electrode 912 continues to record data that it sends back to the
processor 908. The supervising attendant may keep a log of the
positive memory trials such that the corresponding positive
activity at the stimulation site can be re-generated at a later
time by the processor 908. The results of the positive memory
trials along with the corresponding positive activity at the
stimulation site can be archived and saved either within the IPG
(906) or in an external storage device.
As depicted in FIG. 9D, during the regular mode, the long term
electrode 904 records signals which are received by the inference
engine in the processor 908. The inference engine infers a pacing
signal based on the input signal from the long term electrode.
In certain embodiments, the system 900 is configured to detect when
a patient is making or about to make a negative memory recall. The
system 900 includes circuitry capable of detecting inputs received
from the electrodes and/or from external stimuli and determining
based on at least the nature of the inputs, whether the patient is
making or about to make a negative recall. In certain embodiments,
external input in the form of patient or care-giver suggestion, the
system may determine that the patient is making or about to make a
negative memory recall. In response to determining that the patient
is making or about to make a negative memory recall, the system 900
may deliver a pacing signal to induce the neurons in the brain to
generate activity that corresponds to a positive memory recall.
In certain embodiments, the system 900 monitors inputs received
from one or more electrodes and calculates statistics (such as
averages) of the electrical and/or chemical activity of at least a
portion of the brain. Based on the calculated statistics (i.e., if
the calculated statistic crosses a threshold value), the system 900
may predict whether the patient is about to make a positive or
negative memory recall and administer therapy accordingly.
FIG. 10 depicts an implantable electrode 1000 having a long term
electrode component and a short term electrode component. In
particular, the short term component includes small conductive
contact 1002 and the long term component includes a large
conductive contact 1003 that is concentric with the small contact
1002. Each contact 1002 and 1003 has separate conductive tracks
1004 and 1005, respectively. The short term electrode component is
capable of recording electrical activity within the volume 1009 and
including neuron 1012. The long term electrode component is capable
of recording electrical activity within a larger volume 1007 that
includes neurons 1012 and 1014.
As noted above, the order in which the steps of the present method
are performed is purely illustrative in nature. In fact, the steps
can be performed in any order or in parallel, unless otherwise
indicated by the present disclosure. The invention may be embodied
in other specific forms without departing from the spirit or
essential characteristics thereof. The forgoing embodiments are
each therefore to be considered in all respects illustrative,
rather than limiting of the invention.
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